Enantioseparation of planar chiral ferrocenes on cellulose-based chiral stationary phases: Benzoate versus carbamate pendant groups.

In this study, the enantioseparation of 14 planar chiral ferrocenes containing halogen atoms, and methyl, iodoethynyl, phenyl, and 2-naphthyl groups, as substituents, was explored with a cellulose tris(4-methylbenzoate) (CMB)-based chiral column under multimodal elution conditions. n-Hexane/2-propanol (2-PrOH) 95:5 v/v, pure methanol (MeOH), and MeOH/water 90:10 v/v were used as mobile phases (MPs). With CMB, baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.24 to 1.77, whereas only three analytes could be enantioseparated with 1.14 ≤ α ≤ 1.51 on a cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC)-based column, used as a reference for comparison, under the same elution conditions. Pendant group-dependent reversal of the enantiomer elution order was observed in several cases by changing CMB to CDMPC. The impact of analyte and chiral stationary phase (CSP) structure, and MP polarity on the enantioseparation, was evaluated. The two cellulose-based CSPs featured by different pendant groups were also compared in terms of thermodynamics. For this purpose, enthalpy (ΔΔH°), entropy (ΔΔS°) and free energy (ΔΔG°) differences, isoenantioselective temperatures (Tiso ), and enthalpy/entropy ratios (Q), associated with the enantioseparations, were derived from van 't Hoff plots by using n-hexane/2-PrOH 95:5 v/v and methanol/water 90:10 v/v as MPs. With the aim to disclose the functions of the different substituents in mechanisms and noncovalent interactions underlying analyte-selector complex formation at molecular level, electrostatic potential (V) analysis and molecular dynamics simulations were used as computational techniques. On this basis, enantioseparations and related mechanisms were investigated by integrating theoretical and experimental data.

Enantioseparations of polyhalogenated 4,4'-bipyridines on polysaccharide-based chiral stationary phases and molecular dynamics simulations of selector-selectand interactions.

2'-(4-Pyridyl)- and 2'-(4-hydroxyphenyl)-TCIBPs (TCIBP = 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridyl) are chiral compounds that showed interesting inhibition activity against transthyretin fibrillation in vitro. We became interested in their enantioseparation since we noticed that the M-stereoisomer is more effective than the P-enantiomer. Based thereon, we recently reported the enantioseparation of 2'-substituted TCIBP derivatives with amylose-based chiral columns. Following this study, herein we describe the comparative enantioseparation of both 2'-(4-pyridyl)- and 2'-(4-hydroxyphenyl)-TCIBPs on four cellulose phenylcarbamate-based chiral columns aiming to explore the effect of the polymer backbone, as well as the nature and position of substituents on the side groups on the enantioseparability of these compounds. In the frame of this project, the impact of subtle variations of analyte and polysaccharide structures, and mobile phase (MP) polarity on retention and selectivity was evaluated. The effect of temperature on retention and selectivity was also considered, and overall thermodynamic parameters associated with the analyte adsorption onto the CSP surface were derived from van 't Hoff plots. Interesting cases of enantiomer elution order (EEO) reversal were observed. In particular, the EEO was shown to be dependent on polysaccharide backbone, the elution sequence of the two analytes being P-M and M-P on cellulose and amylose tris(3,5-dimethylphenylcarbamate), respectively. In this regard, a theoretical investigation based on molecular dynamics (MD) simulations was performed by using amylose and cellulose tris(3,5-dimethylphenylcarbamate) nonamers as virtual models of the polysaccharide-based selectors. This exploration at the molecular level shed light on the origin of the enantiodiscrimination processes.

Noncovalent interactions in high-performance liquid chromatography enantioseparations on polysaccharide-based chiral selectors.

Designed more than thirty years ago in order to improve and maximize the discrimination capability of native polysaccharides, cellulose- and amylose-based selectors have shown excellent and unequalled performances for the enantioseparation of chiral compounds. The successful story of these chiral selectors relies on a multi-site high-ordered chiral platform which is held up by intramolecular hydrogen bonds (HBs), and makes the polymer able to host and discriminate enantiomers. In this environment, both achiral and stereoselective intermolecular noncovalent interactions play a pivotal role, and HBs, halogen bonds (XBs), dipole-dipole, π-π stacking, steric repulsive, and van der Waals interactions underlie adsorption process and formation of transient diastereomeric assemblies between the polymer and the enantiomer pair. In the last decades, advances in computational chemistry and spectroscopic techniques have improved knowledge of noncovalent interactions, contributing to decode their functions in chemical systems. Significantly, over time the growing interplay between experimental and theoretical approaches has contributed to unravel intermolecular forces underlying selector-selectand association and to understand recognition patterns. On this basis, this review summarizes seminal and representative studies dealing with noncovalent interactions that function in HPLC enantioseparations promoted by cellulose benzoates and phenylcarbamates of amylose and cellulose. The importance of integrating theoretical and experimental approaches to profile mechanisms and interaction patterns is highlighted by discussing focused case studies. In particular, the advantageous utilization of electrostatic potential (V) analysis and molecular dynamics (MD) simulations in this field is evidenced. A systematic compilation of all published literature has not been attempted.

High performance liquid chromatographic enantioseparation of chiral bridged polycyclic compounds on chiralcel OD-H and chiralpak OT(+).

The HPLC enantiomeric separation of 29 racemic bridged polycyclic compounds was examined on commercially available Chiralcel OD-H and Chiralpak OT(+) columns. The separations were evaluated under normal-phase mode (hexane containing mobile phase) for Chiralcel OD-H and under normal-phase as well as under reversed-phase mode (pure MeOH, temperature 5 degrees C) for Chiralpak OT(+). Almost all compounds were resolved either on Chiralcel OD-H or on Chiralpak OT(+), in some cases on both. The use of trifluoroacetic acid (TFA), as modifier of the hexanic mobile phase, had a beneficial effect on the enantioseparation of some polar and acidic compounds on Chiralcel OD-H. The influence of small chemical structural modifications of the analytes on the enantioseparation behavior is discussed. A structure-retention relationship has been observed on both stationary phases. This chromatographic evaluation may provide some information about the chiral recognition mechanism: in the case of Chiralcel OD-H, hydrogen bonding, pi-pi and distereoselective repulsive are supposed to be the major analyte-CSP interactions. In the case of Chiralpak OT(+), a reversed-phase enantioseparation could take place through hydrophobic interactions between the aromatic moiety of the analytes and the chiral propeller structure of the CSP. The synthesis of some unknown racemic bromobenzobicyclo[2.2.1] analytes is also described.

Enantioseparation of fluorinated 3-arylthio-4,4'-bipyridines: Insights into chalcogen and π-hole bonds in high-performance liquid chromatography.

A chalcogen bond (ChB) is a σ-hole-based noncovalent interaction between a Lewis base and an electrophilic element of Group VI (O, S, Se, Te), which behaves as a Lewis acid. Recently, we demonstrated that halogen bond, the more familiar σ-hole-based interaction, is able to promote the enantioseparation of chiral compounds in HPLC environment. On this basis, an investigation to detect ChBs, functioning as stereoselective secondary interactions for HPLC enantioseparations, was started off and the results of this study are described herein. Our investigation also focused on the impact of the perfluorinated aromatic ring as a π-hole donor recognition site. For these purposes, seven atropisomeric fluorinated 3-arylthio-4,4'-bipyridines were designed, synthesized and used as potential ChB donors (ChBDs) with two cellulose-based chiral stationary phases (CSPs) containing carbonyl groups as ChB acceptors (ChBAs). In addition, one and two analogues lacking fluorine and sulphur, respectively, were prepared as terms of comparison. The design of the test analytes was computationally guided. In this regard, electrostatic potentials (EPs) associated with σ- and π-holes were computed and the atomic contributions to the sulphur EP maxima were derived using a molecular space partitioning in terms of Bader's atomic basins. This procedure is akin to the Bader-Gatti electron density source function (SF) decomposition, yet suitably extended to the EP field. For five 3-substituted-4,4'-bipyridines, thermodynamic parameters were derived from van't Hoff plots. Finally, the use of molecular dynamic (MD) simulation to model ChB in cellulose-analyte complexes was explored. Evidences that σ-hole and π-hole interactions can jointly drive HPLC enantioseparations through recognition sites generated by electronic charge depletion emerged from both experimental results and theoretical data.

Halogen bond in high-performance liquid chromatography enantioseparations: Description, features and modelling.

Halogen bond (XB)-driven enantioseparations involve halogen-centred regions of electronic charge depletion (σ-hole) as electrophilic recognition sites. The knowledge in this field is still in its infancy. Indeed, although the influence of halogens on enantioseparation have been often considered, only recently the function of electrophilic halogens (Cl, Br, I) as enantioseparations 'drivers' has been demonstrated by our groups. Further to these studies, in this paper we focus on some unexplored issues. First, as XB-driven chiral recognition mechanisms are at an early stage of comprehension, a theoretical investigation based on a series of 32 molecular dynamic (MD) simulations was performed by using polyhalogenated 4,4'-bipyridines and polysaccharide-based polymers as ligands and receptors, respectively. Enantiomer elution orders (EEOs) were derived from calculations and the theoretical model accounted for some analyte- and chiral stationary phase (CSP)-dependent experimental EEO inversions. Then, the function of halogen-centred σ-holes in competitive systems, presenting also hydrogen bond (HB) centres as recognition sites, was considered. In this regard, Pirkle's enantioseparations of halogenated compounds performed on Whelk-O1 were theoretically re-examined and electrostatic potentials (EPs) associated with both σ-holes on halogens and HB centres were computed and compared. Then, the enantioseparation of halogenated 2-nitro-1-arylethanols was performed on cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) and the influence of halogen substituents on the chromatographic results was evaluated by correlating theoretical and experimental data.

Insights into halogen bond-driven enantioseparations.

Although the halogen bond (XB) has been so far mainly studied in silico and in the solid state, its potential impact in solution is yet to be fully understood. In this study, we describe the first systematic investigation on the halogen bond in solvated environment by high-performance liquid chromatography (HPLC). Thirty three atropisomeric polyhalogenated-4,4'-bipyridines (HBipys), containing Cl, Br and I as substituents, were selected and used as potential XB donors (XBDs) on two cellulose-based chiral stationary phases (CSPs) containing potential XB acceptors (XBAs). The impact of the halogens on the enantiodiscrimination mechanism was investigated and iodine showed a pivotal role on the enantioseparation in non-polar medium. Electrostatic potentials (EPs) were computed to understand the electrostatic component of CSP-analyte interaction. Moreover, van't Hoff studies for ten HBipys were performed and the thermodynamic parameters governing the halogen-dependent enantioseparations are discussed. Finally, a molecular dynamic (MD) simulation is proposed to model halogen bond in polysaccharide-analyte complexes by inclusion of a charged extra point to represent the positive 'σ-hole' on the halogen atom. On the basis of both experimental results and theoretical data, we have profiled the halogen bond as a chemo-, regio-, site- and stereoselective interaction which can work in HPLC environment besides other known interactions based on the complementarity between selector and selectand.

Insights into the impact of shape and electronic properties on the enantioseparation of polyhalogenated 4,4'-bipyridines on polysaccharide-type selectors. Evidence of stereoselective halogen bonding interactions.

Starting from the high-performance liquid chromatography (HPLC) enantioseparation data collected by using twelve polyhalogenated 2,2'-dichloro-3-substituted-5,5'-dihalo-4,4'-bipyridines as test probes on seven polysaccharide-based chiral stationary phases (CSPs) under multimodal elution, the impact of substitution pattern, shape and electronic properties of the molecules on the separation behaviour was investigated through the evaluation of the chromatographic parameters (k, α, Rs) and molecular properties determined by means of quantum chemistry calculations. The computational/chromatographic screening furnished relevant structure-chromatographic behaviour relationships and some molecular interactions involved in the chiral discrimination process could be identified. In particular, a halogen bonding interaction (I(.)O) could reasonably explain the high enantioseparation (α=1.80, Rs=8.2) observed for the 2,2'-dichloro-3,5'-diiodo-5-bromo-4,4'-bipyridine on Lux Cellulose-1. To the best of our knowledge, this is the first report supporting the involvement of a stereoselective halogen bonding interaction in polysaccharide-based CSPs. Moreover, having at disposal a sufficient set of data, the unknown absolute configurations of the eluted enantiomers of 3-methyl-, 3-thiomethyl- and 3-diphenylphosphinoyl-2,2'-dichloro-5,5'-dibromo-4,4'-bipyridines could be deduced by chromatographic correlation with the enantiomer elution order (EEO) of the related compounds of known absolute configuration.

High-performance liquid chromatography enantioseparation of atropisomeric 4,4'-bipyridines on polysaccharide-type chiral stationary phases: Impact of substituents and electronic properties.

The high performance liquid chromatography (HPLC) enantioseparation of eleven atropisomeric 4,4'-bipyridines was performed in the normal and polar organic phase mode using three cellulose-based chiral stationary phases (CSPs), namely Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-4, and two amylose-based CSPs, Chiralpak AD-H and Lux Amylose-2. n-Hexane/2-propanol mixtures and pure ethanol were employed as mobile phases. The combined use of Chiralpak AD-H and Lux Cellulose-2 allowed to enantioseparate all the considered bipyridines. Ten bipyridines were enantioseparated at the multimilligram level allowing the elution sequence determination of the enantiomers as well as their future use for the preparation of homochiral metal organic frameworks (MOFs). Moreover, the performance of the CSPs regarding the same bipyridine was different and dependent on the backbone as well as on the side chain of the polymer. The impact of substitution pattern, shape and electronic properties of the molecules on the separation behavior was investigated through the evaluation of retention factors (k), separation factors (α), resolution (R(s)) and molecular properties determined using density functional theory (DFT) calculations. In this regard, the substituents at the 3,3',5,5' positions of the 4,4'-bipyridyl rings exhibited a pivotal role on the enantioseparation.